title: Prediction of late disease recurrence and extended adjuvant letrozole benefit by the HOXB13/IL17BR biomarker.
abstract: BACKGROUND
  Biomarkers to optimize extended adjuvant endocrine therapy for women with estrogen receptor (ER)-positive breast cancer are limited. The HOXB13/IL17BR (H/I) biomarker predicts recurrence risk in ER-positive, lymph node-negative breast cancer patients. H/I was evaluated in MA.17 trial for prognostic performance for late recurrence and treatment benefit from extended adjuvant letrozole.
  
  
  METHODS
  A prospective-retrospective, nested case-control design of 83 recurrences matched to 166 nonrecurrences from letrozole- and placebo-treated patients within MA.17 was conducted. Expression of H/I within primary tumors was determined by reverse-transcription polymerase chain reaction with a prespecified cutpoint. The predictive ability of H/I for ascertaining benefit from letrozole was determined using multivariable conditional logistic regression including standard clinicopathological factors as covariates. All statistical tests were two-sided.
  
  
  RESULTS
  High H/I was statistically significantly associated with a decrease in late recurrence in patients receiving extended letrozole therapy (odds ratio [OR] = 0.35; 95% confidence interval [CI] = 0.16 to 0.75; P = .007). In an adjusted model with standard clinicopathological factors, high H/I remained statistically significantly associated with patient benefit from letrozole (OR = 0.33; 95% CI = 0.15 to 0.73; P = .006). Reduction in the absolute risk of recurrence at 5 years was 16.5% for patients with high H/I (P = .007). The interaction between H/I and letrozole treatment was statistically significant (P = .03).
  
  
  CONCLUSIONS
  In the absence of extended letrozole therapy, high H/I identifies a subgroup of ER-positive patients disease-free after 5 years of tamoxifen who are at risk for late recurrence. When extended endocrine therapy with letrozole is prescribed, high H/I predicts benefit from therapy and a decreased probability of late disease recurrence.
authors.affiliation: Department of Pathology, Molecular Pathology Unit, Massachusetts General Hospital, Charlestown, MA 02129, USA. dsgroi@partners.org
authors.forename: Dennis C
authors.initials: DC
authors.lastname: Sgroi
authors.forename: Erin
authors.initials: E
authors.lastname: Carney
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Zarrella
authors.forename: Lauren
authors.initials: L
authors.lastname: Steffel
authors.forename: Shemeica N
authors.initials: SN
authors.lastname: Binns
authors.forename: Dianne M
authors.initials: DM
authors.lastname: Finkelstein
authors.forename: Jackie
authors.initials: J
authors.lastname: Szymonifka
authors.forename: Atul K
authors.initials: AK
authors.lastname: Bhan
authors.forename: Lois E
authors.initials: LE
authors.lastname: Shepherd
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Schnabel
authors.forename: Mark G
authors.initials: MG
authors.lastname: Erlander
authors.forename: James N
authors.initials: JN
authors.lastname: Ingle
authors.forename: Peggy
authors.initials: P
authors.lastname: Porter
authors.forename: Hyman B
authors.initials: HB
authors.lastname: Muss
authors.forename: Katherine I
authors.initials: KI
authors.lastname: Pritchard
authors.forename: Dongsheng
authors.initials: D
authors.lastname: Tu
authors.forename: David L
authors.initials: DL
authors.lastname: Rimm
authors.forename: Paul E
authors.initials: PE
authors.lastname: Goss
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D047072:Aromatase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000032:analysis*; D001943:Breast Neoplasms / Q000737:chemistry* / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D016022:Case-Control Studies; D017024:Chemotherapy, Adjuvant; D018572:Disease-Free Survival; D005260:Female; D018398:Homeodomain Proteins / Q000032:analysis*; D006801:Humans; D015994:Incidence; D000077289:Letrozole; D016015:Logistic Models; D008875:Middle Aged; D015999:Multivariate Analysis; D060787:Neoplasm Grading; D009364:Neoplasm Recurrence, Local / Q000453:epidemiology / Q000517:prevention & control; D009367:Neoplasm Staging; D009570:Nitriles / Q000008:administration & dosage / Q000627:therapeutic use*; D011237:Predictive Value of Tests; D011379:Prognosis; D011446:Prospective Studies; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis; D011960:Receptors, Estrogen / Q000032:analysis; D018123:Receptors, Interleukin / Q000032:analysis*; D053722:Receptors, Interleukin-17; D011980:Receptors, Progesterone / Q000032:analysis; D012189:Retrospective Studies; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014230:Triazoles / Q000008:administration & dosage / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D047072:Aromatase Inhibitors; D014408:Biomarkers, Tumor; D018398:Homeodomain Proteins; D000077289:Letrozole; D009570:Nitriles; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D018123:Receptors, Interleukin; D053722:Receptors, Interleukin-17; D011980:Receptors, Progesterone; D014230:Triazoles; C484414:HOXB13 protein, human; C408922:IL17RB protein, human; C508053:ERBB2 protein, human